PROJECT SUMMARY/ABSTRACT Stroke is a major cause of death and disability worldwide and more effective therapies are urgently needed. Unfortunately, all clinical trials that have targeted the primary mechanisms of neuronal injury caused by cerebral ischemia (CI) (i.e. oxidative stress and excitotoxicity) have failed. CI also induces a potent local inflammatory response that leads to progressive damage in the ischemic penumbra. However, emerging evidence suggest that inflammation may also initiate key post-stroke repair processes including angiogenesis leading to long-term functional recovery. For these reasons we propose that inflammation is an attractive therapeutic target for stroke recovery. In support of this, we have recently shown that endogenous post-stroke brain upregulation of the proinflammatory cytokine interleukin-1 (IL-1) isoform IL-1? is tightly regulated in a cell-specific fashion (microglia acutely and platelets chronically) suggesting that it could play important roles in both injury and repair, respectively. Furthermore, we now demonstrate that delayed (3 day) post-stroke administration of IL-1? promoted post-stroke angiogenesis in mice. This may occur, at least in part, as the result of IL-1?-induced generation of the proangiogenic extracellular matrix fragment perlecan LG3. Furthermore, as LG3 has known neuroprotective actions, we hypothesize that IL-1? could be both neuroprotective and neurorestorative in ischemic stroke. In support of this hypothesis, preliminary results suggest that IL-1? administered systemically (IV) or intra-arterially (IA) immediately after reperfusion in mice subjected to transient middle cerebral artery occlusion is well tolerated, profoundly neuroprotective and functionally restorative. Therefore, we hypothesize that IL-1? may represent a novel neuroprotective agent for ischemic stroke. To investigate the neuroprotective potential and mechanism(s) of action of IL-1? in experimental ischemic stroke, we propose the following aims: Aim 1: Determine the role of acute and chronic endogenous IL-1? in ischemic stroke. Aim 2: Determine the therapeutic potential of IL-1? in experimental ischemic stroke. Aim 3: Determine the neuroprotective mechanism(s) of IL-1? action. Successful completion of these studies will increase our understanding of the role of endogenous IL-1? at different stages after stroke, determine its therapeutic potential and mechanism(s) of action, and support IL-1? as a promising novel stroke therapy.